Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Summary

Malaria is a sickness caused by a germ that can get into a person's body when a mosquito
bites them. It can cause fever, headache, body aches and weakness. It can even cause death,
especially in children. When malaria is treated with the appropriate medicine(s), it can be
cured completely. The purpose of this study is to find out if it is better to use
chloroquine alone or in combination with another drug to most effectively treat malaria.
About 640 children with malaria, aged 6 months to 5 years of age, from the Blantyre Malaria
Project Research Clinic at the Ndirande Health Center in Malawi will be in the study. They
will be treated with either chloroquine alone or a combination of chloroquine plus another
medication (azithromycin or artesunate or atovaquone-proguanil) every time they get malaria
for a year. Blood samples will be collected and tested at least every 4 weeks. Participants
will be involved in the study for 1 year.

Clinical Details

Official title: A Longitudinal Study of Chloroquine as Monotherapy or in Combination With Artesunate, Azithromycin or Atovaquone-Proguanil to Treat Malaria in Children in Blantyre, Malawi

Detailed description:
Combination therapy is becoming the mainstay of malaria treatment. In general, the goal of
combination therapy is to treat resistant infections successfully and to prevent the
emergence and spread of resistance. The antimalarial combination therapies currently in use
were not designed based on optimal pairing of drugs to deter the development and spread of
parasite resistance to the individual partner drugs in settings of high malaria
transmission. Careful studies are needed to identify the pharmacokinetic and pharmacodynamic
properties of drug combinations that will deter resistance and prolong the useful
therapeutic life of the next generation of antimalarial drug combinations. Current in vivo
methods for measuring antimalarial drug efficacy in high-transmission areas use a 14 or
28-day follow-up period, but a single episode study misses several critical factors in
assessing the efficacy and impact of antimalarial treatment. When follow-up is extended
beyond 28 days, more cases of apparent resistance or treatment failure are found.
Single-episode studies cannot assess the impact of therapy on the incidence of malaria over
time. These limitations of standard in vivo studies have led the investigators to advocate
longitudinal studies of drug efficacy. In addition to measuring efficacy of individual
treatments, longitudinal studies measure sustained efficacy with repeated use of the same
regimen over time, a scenario that more accurately reflects the real-life use of
anti-malarial medication. The primary outcome of interest is the incidence of malaria
episodes, as well as the secondary outcomes of anemia and severe malaria, are all highly
relevant to public health policy-makers, as they reflect not only the burden of disease but
also the utilization of health resources. Longitudinal studies also permit assessment of how
pharmacokinetic properties of drugs affect the incidence of treatment episodes. This is a
randomized, open-label, longitudinal drug efficacy trial. Participants will include 640
children, aged 6 months to 5 years, who are found to have uncomplicated malaria at the
Blantyre Malaria Project Research Clinic at the Ndirande Health Centre in Blantyre, Malawi.
After enrollment, participants will be randomized to one of four treatment arms: chloroquine
alone or chloroquine in combination with artesunate, atovaquone-proguanil (AP), or
azithromycin. The treatment outcome will be assessed through a standard 28-day efficacy
study. Participants will subsequently be evaluated every 4 weeks and encouraged to return to
the study clinic any time they are ill during the course of one year. If a new episode of
uncomplicated malaria is diagnosed, the participant will receive the same therapy as
assigned on enrollment. Polymerase chain reaction-corrected 28-day efficacy will be
evaluated for each treatment episode. The primary study objective is to compare annual
incidence of malaria clinical episodes. Secondary objectives are to: assess anti-malarial
drug efficacy at first administration, by treatment arm; assess anti-malarial drug efficacy
during subsequent episodes of malaria, by treatment arm; measure prevalence of chloroquine
resistant parasites during the trial, by treatment arm; assess effect of each treatment arm
on anemia at the end of study participation; assess safety of these drugs with repeated use;
determine the chloroquine blood levels at which chloroquine sensitive and resistant
parasites are able to cause infection; assess the effect of population movements on the risk
of malaria infection; and assess the spatial patterns and the environmental determinants of
malaria infection. Participants will be involved in study rela

Eligibility

Minimum age: 6 Months.
Maximum age: 5 Years.
Gender(s): Both.

Criteria:

Inclusion Criteria:

- Subjects aged greater than or equal to 6 months to 5 years presenting to Ndirande

Health Centre with signs or symptoms consistent with malaria including, but not
limited to, one or more of the following:
1. fever at the time of evaluation (axillary temperature greater than or equal to
37. 5 degrees Celsius by digital thermometer)
2. report of fever within the last two days
3. clinically profound anemia (conjunctival or palmar pallor)
4. headache
5. body aches
6. abdominal pain
7. decreased intake of food or fluids
8. weakness